山豆根对小鼠大脑毒性作用的组学和生物信息学研究Omics and bioinformatics studies of the brain toxicity of Sophorae Tonkinensis Radix et Rhizoma in mice
张帅男,李红美,李煦照
ZHANG Shuainan,LI Hongmei,LI Xuzhao
摘要(Abstract):
目的 代谢组学、蛋白质组学和生物信息学被用于分析山豆根脑毒性的作用机制及物质基础。方法 运用代谢组学和蛋白质组学分析山豆根干预脑组织后的差异表达代谢物和蛋白质。随后,对这些内源性靶点在MetaboAnalyst数据库中进行联合通路分析。STITCH数据库和STRING数据库被用于筛选响应毒性靶点的物质基础。结果 组学结果表明,经山豆根干预后,小鼠脑组织中的38个代谢物和293个蛋白质发生差异表达。其中,11个差异表达的代谢物和21个差异表达的蛋白质参与了8个显著调节通路。生物信息学表明,24个成分有可能干预了18个毒性靶点的表达。结论 多个靶点参与了山豆根诱导的脑毒性,它们的异常表达有诱导神经兴奋性毒性、智力迟钝、记忆下降、皮质损伤等发生的可能性。多种成分有可能成为响应这些作用的物质基础。
Objective Metabolomics, proteomics, and bioinformatics were used to analyze the mechanism and material basis of the brain toxicity induced by Sophorae Tonkinensis radix et rhizome(ST).Methods Metabonomics and proteomics were applied to analyze the differentially expressed metabolites and proteins in brain tissue after treatment with ST.Subsequently, the endogenous targets were used for joint pathway analysis in MetaboAnalyst.STITCH and STRING database were applied to screen the material basis responsible for the toxic targets.Results Omics revealed that 38 metabolites and 293 proteins were differentially expressed after the treatment with ST,out of which 11 metabolites and 21 proteins were significantly enriched in 8 pathways.Bioinformatics showed that 24 compounds might interfere with the expressions of 18 toxic targets of ST.Conclusion Multiple targets are involved in the brain toxicity induced by ST,whose dysregulation may show the tendency to induce the occurrence of neuroexcitatory toxicity, mental retardation, memory decline, and cortical damage, etc.Multiple compounds may be the toxic material basis in response to these effects.
关键词(KeyWords):
山豆根;脑毒性;代谢组学;蛋白质组学;生物信息学
Sophora tonkinensis Gagnep.;brain toxicity;metabonomics;proteomics;bioinformatics
基金项目(Foundation): 国家自然科学基金项目(81960749);; 贵州中医药大学研究生教育创新计划重点项目(YCXZR2020002)
作者(Author):
张帅男,李红美,李煦照
ZHANG Shuainan,LI Hongmei,LI Xuzhao
DOI: 10.14066/j.cnki.cn21-1349/r.2021.0613
参考文献(References):
- [1] Chinese Pharmacopoeia Commission.Chinese Pharmacopoeia:Part 1 (中华人民共和国药典:一部)[M].Beijing:Chinese Medical Science Press,2020:28.
- [2] ZHANG S N,LI H M,LI X Z,et al.Integrated omics and bioinformatics analyses for the toxic mechanism and material basis of Sophorae Tonkinensis radix et rhizome-induced hepatotoxicity [J].J Pharm Biomed Anal,2021,198:113994.
- [3] FAN F,HE J X,NIU H H,et al.Diagnosis and treatment report and clinical experience of 5 cases of children with radix sophorae subprostratae poisoning [J].Clinical Research and Practice (临床医学研究与实践),2021,6(7):26-28.
- [4] ZHANG S N,LI X Z,TAN L Y,et al.A review of pharmacological and toxicological effects of Sophora tonkinensis with bioinformatics prediction [J].Am J Chin Med,2021,49(2):359-389
- [5] ZHANG S N,LI X Z,YANG X Y.Drug-likeness prediction of chemical constituents isolated from Chinese materia medica Ciwujia [J].J Ethnopharmacol,2017,198:131-138.
- [6] LI X Z,ZHANG S N,YANG X Y.Combination of cheminformatics and bioinformatics to explore the chemical basis of the rhizomes and aerial parts of Dioscorea nipponica Makino [J].J Pharm Pharmacol,2017,69(12):1846-1857.
- [7] LI X Z,HUANG H J,ZHANG S N,et al.Label-free quantitative proteomics positions the effects and mechanisms of Herba Lysimachiae on synovial diseases based on biolabel-led research pattern[J].J Chromatogr B Analyt Technol Biomed Life Sci,2020,1138:121969.
- [8] ZHANG M W.Clinical observation on the toxicity of Sophorae Tonkinensis Radix et Rhizome—34 cases of poisoning [J].J New Chin Med (新中医),1998 (5):57.
- [9] VAN HEEKE G,SCHUSTER S M.The N-terminal cysteine of human asparagine synthetase is essential for glutamine-dependent activity [J].J Biol Chem,1989,264(33):19475-19477.
- [10] POLIS B,SAMSON A O.Alzheimer′s disease[M].Brisbane:Codon Publications,2019:1-22.
- [11] PRAKASH O,LUKIW W J,PERUZZI F,et al.Gliomas and seizures [J].Med Hypotheses,2012,79(5):622-626.
- [12] LI S,STYS P K.Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter [J].J Neurosci,2000,20(3):1190-1198.
- [13] BUSTOS F J,AMPUERO E,JURY N,et al.Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer′s disease mice[J].Brain,2017,140(12):3252-3268.
- [14] KAYSER M A.Inherited metabolic diseases in neurodevelopmental and neurobehavioral disorders [J].Semin Pediatr Neurol,2008,15(3):127-131.
- [15] XIE X,JANKAUSKAS R,MAZARI A M A,et al.β-actin regulates a heterochromatin landscape essential for optimal induction of neuronal programs during direct reprograming [J].PLoS Genet,2018,14(12):e1007846.
- [16] ERRANTE P R,CONDINO-NETO A.Cellular primary immunodeficiencies[M].Cham:Springer,2012:97-176.
- [17] ARNAUD L,BALLIF B A,F?RSTER E,et al.Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development [J].Curr Biol,2003,13(1):9-17.
- [18] BACH S A,DE SIQUEIRA L V,MüLLER A P,et al.Dietary omega-3 deficiency reduces BDNF content and activation NMDA receptor and Fyn in dorsal hippocampus:implications on persistence of long-term memory in rats [J].Nutr Neurosci,2014,17(4):186-192.
- [19] MONCADA S,HIGGS A.The L-arginine-nitric oxide pathway [J].N Engl J Med,1993,329(27):2002-2012.
- [20] REITH J,BENKELFAT C,SHERWIN A,et al.Elevated dopa decarboxylase activity in living brain of patients with psychosis [J].Proc Natl Acad Sci U S A,1994,91(24):11651-11654.
- [21] WAGNER B,NATARAJAN A,GRüNAUG S,et al.Neuronal survival depends on EGFR signaling in cortical but not midbrain astrocytes [J].Embo J,2006,25(4):752-762.
- [22] RUDDICK J P,EVANS A K,NUTT D J,et al.Tryptophan metabolism in the central nervous system:medical implications [J].Expert Rev Mol Med,2006,8(20):1-27.
- [23] LEE H J,RAO J S,RAPOPORT S I,et al.Antimanic therapies target brain arachidonic acid signaling:lessons learned about the regulation of brain fatty acid metabolism [J].Prostaglandins Leukot Essent Fatty Acids,2007,77(5/6):239-246.
- [24] RAO J S,RAPOPORT S I,KIM H W.Altered neuroinflammatory,arachidonic acid cascade and synaptic markers in postmortem Alzheimer′s disease brain [J].Transl Psychiatry,2011,1(8):e31.
- [25] LOVELESS R,TENG Y.Targeting WASF3 signaling in metastatic cancer [J].Int J Mol Sci,2021,22(2):836.
- [26] ZHU W P,LIU Z Y,ZHAO Y M,et al.Dihydropyrimidine dehydrogenase predicts survival and response to interferon-α in hepatocellular carcinoma [J].Cell Death Dis,2018,9(2):69.
- [27] BELCHEVA M M,WONG Y H,Coscia C J.Evidence for transduction of mu but not kappa opioid modulation of extracellular signal-regulated kinase activity by G(z) and G(12) proteins [J].Cell Signal,2000,12(7):481-489.
- [28] LU K T,WANG Y W,WO Y Y,et al.Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury[J].Neurosci Lett,2005,386(1):40-45.
- [29] MOK C F,XIE C M,SHAM K W,et al.1,4-Dihydroxy-2-naphthoic acid induces apoptosis in human keratinocyte:potential application for psoriasis treatment[J].Evid Based Complement Alternat Med,2013,2013:792840.
- [30] LEIPNITZ G,SEMINOTTI B,HAUBRICH J,et al.Evidence that 3-hydroxy-3-methylglutaric acid promotes lipid and protein oxidative damage and reduces the nonenzymatic antioxidant defenses in rat cerebral cortex [J].J Neurosci Res,2008,86(3):683-693.
- [31] ANWAR-MOHAMED A,EL-KADI A O.Induction of cytochrome P450 1a1 by the food flavoring agent,maltol [J].Toxicol In Vitro,2007,21(4):685-690.
- [32] KLEMM P,HECKER M,STOCKHAUSEN H,et al.Inhibition by N-acetyl-5-hydroxytryptamine of nitric oxide synthase expression in cultured cells and in the anaesthetized rat [J].Br J Pharmacol,1995,115(7):1175-1181.
- [33] WANG B W,LIAO W N,CHANG C T,et al.Facilitation of glutamate release by nicotine involves the activation of a Ca2+/calmodulin signaling pathway in rat prefrontal cortex nerve terminals[J].Synapse,2006,59(8):491-501.